The focus of this project has been to understand the mechanism(s) responsible for the induction of both immunity and tolerance to pancreatic islet allografts. The emphasis of this project has continued to shift towards understanding the latter process, the nature of cellular interactions, that result in tolerance induction. Results generated from the previous fimding period have identified a variety of therapies that can result in long-term islet allograft survival. These studies have culminated in the recent finding that combined treatment with a non-lymphocyte-depleting regimen of anti-CD154 plus anti-LFA-1 (CD11a) is profoundly efficacious in a high-responder mouse strain (C57B1/6) and results in 'dominant', transferable tolerance to islet allografts. The general conceptual framework of these studies is that the induction of peripheral allograft tolerance is largely a recapitulation of self-tolerance. Based on the study of peripheral self-tolerance and our previous results in islet allograft tolerance, this project examines three general tenets of 'dominant' tolerance: (1) 'Dominant' regulatory transplantation tolerance shares several features with regulatory self-tolerance, (2) Regulatory tolerance requires "indirect' (host MHC class II-restricted) T cell reactivity, and (3) Tolerance to islet aIIografts does not require the elimination of potentially graft destructive T cells. Experiments described in this renewal application are designed to test (i.e. support or disprove) the implications of these three general tenets through the following specific aims: Specific Aim I: Determine the contribution of a 'gain of function' (generation of active regulation) to the tolerant state: This aim will test the general hypothesis that 'dominant' transplantation tolerance involves a recapitulation of T cell dependent regulatory self-tolerance; Specific Aim II: Determine the role of host-MHC class II-restricted 'indirect' antigen recognition for the expression of 'dominant' tolerance. This aim will test the hypothesis that dominant tolerance requires indirect, host MHC class II-restricted antigen recognition; Specific Aim III: Determine the contribution of a 'loss of function' (deletion/anergy) to the tolerant state. This aim will critically test the hypothesis that tolerance does not require a loss in graft-destructive T cells in vivo. This aim will determine whether defined, graft-reactive CD8 T cells must be eliminated/inactivated in order to achieve tolerance.